Candida and Candidiasis: The Cell Wall as a Potential Molecular Target for Antifungal Therapy

Gozalbo, Daniel; Roig, Patricia; Villamón, Eva; Gil, M. Luisa

doi:10.2174/1568005043341046

Cited by 62 publications

(47 citation statements)

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“…Consequently, there is a drive to develop safe, cytotoxic antifungal drugs. Because of the importance of the fungal cell wall for survival and morphogenesis and because human cells do not have walls, this structure is regarded as a prime target for the development of safe and effective antifungal agents (38,99). Saccharomyces cerevisiae is considered a good model for the study of fungal cell wall biogenesis.…”

Section: Cell Wall As a Target For Antifungal Drug Developmentmentioning

confidence: 99%

Cell Wall Integrity Signaling inSaccharomyces cerevisiae

Levin¹

2005

Microbiol Mol Biol Rev

1,061

1,227

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The yeast cell wall is a highly dynamic structure that is responsible for protecting the cell from rapid changes in external osmotic potential. The wall is also critical for cell expansion during growth and morphogenesis. This review discusses recent advances in understanding the various signal transduction pathways that allow cells to monitor the state of the cell wall and respond to environmental challenges to this structure. The cell wall integrity signaling pathway controlled by the small G-protein Rho1 is principally responsible for orchestrating changes to the cell wall periodically through the cell cycle and in response to various forms of cell wall stress. This signaling pathway acts through direct control of wall biosynthetic enzymes, transcriptional regulation of cell wall-related genes, and polarization of the actin cytoskeleton. However, additional signaling pathways interface both with the cell wall integrity signaling pathway and with the actin cytoskeleton to coordinate polarized secretion with cell wall expansion. These include Ca2+ signaling, phosphatidylinositide signaling at the plasma membrane, sphingoid base signaling through the Pkh1 and -2 protein kinases, Tor kinase signaling, and pathways controlled by the Rho3, Rho4, and Cdc42 G-proteins

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Section: Cell Wall As a Target For Antifungal Drug Developmentmentioning

confidence: 99%

Cell Wall Integrity Signaling inSaccharomyces cerevisiae

Levin¹

2005

Microbiol Mol Biol Rev

1,061

1,227

View full text Add to dashboard Cite

show abstract

“…The antifungal agents available to treat systemic candidiasis are limited, and their clinical usefulness is hampered by their safety, due to undesirable side effects on patients, and by the emergence of resistances that parallels their clinical use (Sanglard and Odds 2002;Gozalbo et al 2004). Therefore, development of new antifungal drugs as well as new strategies to control Candida infections are needed.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, development of new antifungal drugs as well as new strategies to control Candida infections are needed. There is increasing evidence, from clinical observations and animal models of candidiasis, indicating that some Candida-specific antibodies can be immunoprotective during infection, thus showing the viability of an immunotherapy and/or vaccine approach for the treatment and management of candidiasis Matthews and Burnie 2001;Gozalbo et al 2004). Protection against disseminated candidiasis has been reported following both active vaccination and passive transfer of antibodies (Cardenas-Freitag et al 1999;Han et al 1999Han et al , 2000Matthews and Burnie 2004;Bromuro et al 2002;Montagnoli et al 2004;Ibrahim et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the usefulness of anti-glyceraldehyde-3-phosphate dehydrogenase antibodies as a treatment for invasive candidiasis in a murine model

Gil

Dagan

Eren

et al. 2006

Antonie Van Leeuwenhoek

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We have evaluated the effect of antibodies against the Candida albicans glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a potential immunotherapeutic treatment for acute invasive candidiasis in a murine model of infection. Three different approaches were assayed: (i) active immunization of mice using recombinant His-tagged GAPDH, (ii) treatment of fungal yeast cells with anti-GAPDH antibodies prior to infection, and (iii) passive transfer of polyclonal anti-GAPDH antibodies. Results showed that all three approaches, although tending to show a slight beneficial effect in some instances, fail to have a relevant and statistically significant effect on the infection course, determined by survival curves and fungal burden in kidneys. This suggests that the cell wall-associated GAPDH of C. albicans, despite its potential role in virulence, does not appear to be a suitable target protein for the development of immunotherapeutic strategies against candidiasis, although further studies may be required to confirm this observation.

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“…The fungal cell wall represents an excellent drug target, since it is structurally unique, its integrity is a precondition for the survival of the fungus, and it represents an essential barrier for protection against host defense mechanisms (1,8,9,16). The fungal envelope consists of a framework of glycostructures, e.g., chitin and glucans, and a set of cell wall-associated proteins (1).…”

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confidence: 99%

The Putative α-1,2-Mannosyltransferase AfMnt1 of the Opportunistic Fungal Pathogen Aspergillus fumigatus Is Required for Cell Wall Stability and Full Virulence

et al. 2008

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Proteins entering the eukaryotic secretory pathway commonly are glycosylated. Important steps in this posttranslational modification are carried out by mannosyltransferases. In this study, we investigated the putative ␣-1,2-mannosyltransferase AfMnt1 of the human pathogenic mold Aspergillus fumigatus. AfMnt1 belongs to a family of enzymes that comprises nine members in Saccharomyces cerevisiae but only three in A. fumigatus. A ⌬afmnt1 mutant is viable and grows normally at 37°C, but its hyphal cell wall appears to be thinner than that of the parental strain. The lack of AfMnt1 leads to a higher sensitivity to calcofluor white and Congo red but not to sodium dodecyl sulfate. The growth of the mutant is abrogated at 48°C but can be restored by osmotic stabilization. The resulting colonies remain white due to a defect in the formation of conidia. Electron and immunofluorescence microscopy further revealed that the observed growth defect of the mutant at 48°C can be attributed to cell wall instability resulting in leakage at the hyphal tips. Using a red fluorescence fusion protein, we localized AfMnt1 in compact, brefeldin A-sensitive organelles that most likely represent fungal Golgi equivalents. The tumor necrosis factor alpha response of murine macrophages to hyphae was not affected by the lack of the afmnt1 gene, but the corresponding mutant was attenuated in a mouse model of infection. This and the increased sensitivity of the ⌬afmnt1 mutant to azoles, antifungal agents that currently are used to treat Aspergillus infections, suggest that ␣-1,2-mannosyltransferases are interesting targets for novel antifungal drugs.

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Candida and Candidiasis: The Cell Wall as a Potential Molecular Target for Antifungal Therapy

Cited by 62 publications

References 0 publications

Cell Wall Integrity Signaling inSaccharomyces cerevisiae

Cell Wall Integrity Signaling inSaccharomyces cerevisiae

Evaluation of the usefulness of anti-glyceraldehyde-3-phosphate dehydrogenase antibodies as a treatment for invasive candidiasis in a murine model

The Putative α-1,2-Mannosyltransferase AfMnt1 of the Opportunistic Fungal Pathogen Aspergillus fumigatus Is Required for Cell Wall Stability and Full Virulence

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